Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the welldocumented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immunesuppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.
Bibliographical noteFunding Information:
J.W. Tyner reports grants from NCI during the conduct of the study, grants from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Acerta, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, Tolero, and other support from Recludix outside the submitted work. L.B. Baughn reports grants from NCI during the conduct of the study and grants from NCI outside the submitted work. J.J. Alumkal reports personal fees and other support from Astellas Pharma and other support from Astellas Pharma during the conduct of the study; personal fees from Dendreon and Bristol Myers Squib, personal fees and other support from Merck, and other support from Beactica outside the submitted work. T.G. Bivona reports grants and other support from Revolution Medicines; grants from Kinnate, Strategia, Verastem; other support from Relay, Rain, Engine, Scorpion, Fore, and Springworks outside the submitted work. B.J. Druker reports grants from NIH NCI U54 and other support from Howard Hughes Medical Institute during the conduct of the study; personal fees from Aptose Biosciences, Iterion Therapeutics, Blueprint Medicines, Burroughs Wellcome Fund, Cepheid, GRAIL, Enliven Therapeutics, Nemucore Medical Innovations, VB Therapeutics, Vincerx Pharma, Vivid Biosciences, Beat AML LLC, CureOne, Gilead Sciences, ICON, formerly Molecular MD, RUNX1 Research Project, AstraZeneca, Aileron, Inc., Amgen, Novartis, Recludix Pharma Inc., and Therapy Architects outside the submitted work; in addition, B.J. Druker has a patent for Treatment of Gastrointestinal Stromal Tumors issued and with royalties paid from Novartis, a patent for Monoclonal antiphosphotyrosine antibody 4G10 licensed to Merck & Co., Mutated ABL Kinase Domains licensed to Sun Pharma, Methods Apparatuses and Sustems for Detecting and Quantifying Phosphoproteins issued, Methods, Systems, and Apparatuses for Quantitative Analysis of Heterogeneous Biomarker Distribution issued, Methods, Systems, and Apparatuses for Quantitative Analysis of Heterogeneous Biomarker Distribution issued, Detection of Gleevec Resistant Mutations issued, Detection of Gleevec Resistant Mutations issued, and Detection of Gleevec resistance issued. P.S. Nelson reports grants from NIH/NCI during the conduct of the study, personal fees from Bristol Myers Squibb, and grants from Janssen outside the submitted work. C.L. Sawyers reports grants from NCI U54 Moonshot Grant during the conduct of the study; personal fees from Novartis, ORIC, Arsenal, Beigene, Blueprint, KSQ, Nextech, Column Group, PMV, Foghorn, and Housey Pharma outside the submitted work; C.L. Sawyers serves on the Board of Directors of Novartis, is a co-founder of ORIC Pharmaceuticals and coinventor of enzalutamide and apalutamide. C.L. Sawyers is a science advisor to Arsenal, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, and PMV. C.D. Willey reports grants from NIH/NCI during the conduct of the study; grants from NIH/NCI, AACR-Novocure, OMS Foundation; grants and personal fees from Varian Medical Systems; personal fees from LifeNet Health; and personal fees from ACRO outside the submitted work; in addition, C.D. Willey has a patent for US Letters Patent No. 8,129,356 issued. No disclosures were reported by the other authors.
The work of the Drug Resistance and Sensitivity Network is supported by the NCI Cancer Moonshot under awards U54 CA224019, U54 CA224079, U54 CA224081, U54 CA224018, U54 CA224068, U01 CA217885-03S1, R01 CA131261-09S2, U54 CA224065-02, R01 CA207757-03S1, R01 CA192844-04S1, R37 CA230617-02S1, U01 CA223976-03S1, P50 CA186786-07S1, U01 CA231776-03S1, R01 CA175397-07S1, and U24 CA232979.
© 2022 The Authors; Published by the American Association for Cancer Research.